Genetic Variant PGAP2:p.Arg238Ser (chr11-3825023-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001346403.1(PGAP2):c.791C>A(p.Ser264*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S264S) has been classified as Likely pathogenic. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PGAP2
NM_001346403.1 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.75

Publications

0 publications found

Variant links:

Genes affected

PGAP2 (HGNC:17893): (post-GPI attachment to proteins 2) The protein encoded by this gene plays a role in the maturation of glycosylphosphatidylinositol (GPI) anchors on GPI-anchored proteins. Mutations in this gene are associated with an autosomal recessive syndrome characterized by hyperphosphatasia and intellectual disability. [provided by RefSeq, Jul 2017]

PGAP2 Gene-Disease associations (from GenCC):

hyperphosphatasia with intellectual disability syndrome 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
hyperphosphatasia-intellectual disability syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PGAP2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346403.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PGAP2	NM_014489.4	MANE Select	c.712C>A	p.Arg238Ser	missense	Exon 6 of 7	NP_055304.1	Q9UHJ9-2
PGAP2	NM_001346403.1		c.791C>A	p.Ser264*	stop_gained	Exon 7 of 8	NP_001333332.1
PGAP2	NM_001256237.2		c.608C>A	p.Ser203*	stop_gained	Exon 6 of 7	NP_001243166.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PGAP2	ENST00000278243.9	TSL:1 MANE Select	c.712C>A	p.Arg238Ser	missense	Exon 6 of 7	ENSP00000278243.4	Q9UHJ9-2
PGAP2	ENST00000300730.10	TSL:1	c.688C>A	p.Arg230Ser	missense	Exon 6 of 7	ENSP00000300730.6	Q9UHJ9-5
PGAP2	ENST00000396993.8	TSL:1	c.61C>A	p.Arg21Ser	missense	Exon 5 of 6	ENSP00000380190.6	A8MZF5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111968

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.065

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Benign

0.17

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.78

MetaRNN

Benign

0.20

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.9

PhyloP100

1.7

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.5

REVEL

Benign

0.15

Sift

Benign

0.19

Sift4G

Benign

0.52

Polyphen

0.75

Vest4

0.59

MutPred

0.56

Loss of MoRF binding (P = 0.0331)

MVP

0.47

MPC

0.44

ClinPred

0.64

GERP RS

5.3

Varity_R

0.21

gMVP

0.60

Mutation Taster

=131/69

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.41

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over